Antitussive compositions



United States Patent 3,103,041 ANTITUSSIVE COMPOSITIONS Nathan Weiner, Rego Park, N.Y., assignor to Endo Laboratories, Inc., Richmond Hill, N.Y., a corporation of New York No Drawing. Filed May 11, 1960, Ser. No. 28,247 13 Claims. (Cl. 167-55) suppressing bronchial stimulation and liquefaction of mucous which will accumulate in the lungs.

Muscular spasm, particularly in the bronchial musculature, prevents the sufferer of a cough from eliminating viscous secretions which accumulate under those pathological conditions, in consequence of the adverse eifect on the cough reflex which assists in the expulsion of such mucous plugs.

In general, the usual type of antispasmodic which relaxes the spasm of smooth skeletal muscle is not effective in relieving the spasm of the bronchial tree.

l have unexpectedly found that a particular type of antispasmodic can relieve spasms braught about by such antitussives. This particular type of antispasmodic is especially effective in combination with antitussive drugs which do not belong to the class of opium derivatives, and are non-addicting on continued use. The mentioned antispasmodics are members of the class of compounds which are synthetic esters of tropine and quaternized salts of such esters.

I have found that this particular class of ant-ispasmodics when combined with the mentioned non-narcotic antitussives, produces an antitussive action which is superior to that of the antitussive per se, and prevents the undesirable and discomforting side actions, named above, of the antitussive.

Accordingly, it is among the principal objects of this invention to provide novel compositions having superior antitussive properties.

Another object is to provide a composition which produces antitussive action without the concomitant undesirable side effects ordinarily attending the action of antitussives.

A still further object is to provide compositions which are combinations of antitussives and a particular type of 'antispasmodic.

An even further object is to provide compositions which are combinations of antitussives and non-addicting antispasmodics, said antispasmodi-cs being synthetic esters of tropine and quaternized salts thereof.

The following are examples and preferred embodiments in accordance with this invention:

Example 1 20 parts of dextro-3-methoxy-N-methyl morphinan hydrobromide is mixed with one part of homatropine methy-lbromide by weight. This mixture is added to a syrup containing 25 parts of pyrilamine maleate in a syrup base, containing sucrose and sor-bitol and flavors, at such a concentration that in each 5 cc. there is mgs. of dextro-3- methoxy-N-methyl rnorphinan hydrobromide and 0.5 mg. of homatropine methylbromide. This composition proice duces a rapid relief of the cough reflex in persons who suffer from a cough due to the symptoms of the common cold. The person is also relieved from the unpleasant constipating action and tightness of the chest which are concurrent symptoms of the common cold.

Example 2 A tablet granulation is prepared with the following ingredients:

Grams Dextro-3-methoxy-N-methyl morphinan hydrobromide Homatropine methylbromide 20 Lactose 1,420 Starch 350 Sucrose 70 Magnesium stearate 10 The powders are ground and mixed and converted into a granulation by the usual techniques known to the art for the manufacture of compressed tablets. The tablets are then compressed at such a diameter and gauge that the final weight of the compressed tablet is 0.202 gm. per tablet; each tablet containing 15 mg. of the antitussive ingredient (dextro-3-methoxy-N-methyl morphinan hydrobromide) and 2 mg. of homatropine methylbromide.

These tablets are applicable to the treatment of the symptoms of a cold, namely cough and tightness of the chest, as described in Example 1.

Example 3 Example 4 A syrup is prepared with the following ingredients: Noscapine base "grams" 2 Citric acid do 5 Homatropine methylbromide do 0.2 Ammonium chloride do 16 Flavoring oils ml. 30 Water ml 10 Sugar syrup, U.S.P., q.s. 1,000 ml.

The syrup contains, in each teaspoon-ful, 10 mg. of the non-narcotic antitussive agent, noscapine, and 1 mg. of the antispasmodic agent, homatropine methylbromide. This syrup produces excellent relief of the cough reflex, which is stimulated by the irritation of the symptoms of the common cold. However, the tightness of the chest and constipation, which are concomitant symptoms of this disease, are likewise relieved.

Example 5 Example 6 In a fashion similar to Example 3, tablets are prepared which contain, per tablet, 15 mg. of the non-narcotic antitussive, noscapine, and 5 mg. of the synthetic spasmolytic agent, dipropyl acetyl tropinium methylbrornide.

When used for the relief of cough due to colds, as the preparation of Example 3, they effectively suppress the cough and relieve the concomitant, uncomfortable intestinal symptoms of the common cold.

Example 7 A syrup is prepared, as in Example 1, containing per teaspoonful, 7.25 mg. of Z-(diethylamino-ethoxy) ethyl phenyl-cyclopentyl-l-carboxylate citrate and 0.5 mg. of homatropine methylbromide.

When administered to one suffering from the symptoms of the common cold, the irritating cough which accompanies this condition is suppressed, the tightness of the chest, which is produced by the antitussive drug, is relieved, and the person does not suffer from constipation.

Example 8 A tablet is prepared in accordance with the instructions of Example 2, except that the non-narcotic antitussive in this preparation is Z-(diethylamino-ethoxy) ethyl phenyl-cyclopentyl-l-carboxylate citrate (7.25 mg. per tablet), and the antispasmodic which relieves the side reactions of the antitussive, is the dipropyl acetyl ester citrate of tropine. This is included in the granulation in such a quantity that each tablet contains 2 mg. of antispasmodic.

.The effects produced are similar to those described for the previous examples.

Example 9 A tablet is prepared in accordance with the instructions of Example 2, except that the non-narcotic antitussive is included in the granulation in such quantities that each tablet contains 25 mg. of 2-(diethylamino-ethoxy) ethyl phenyl-cyclopentyl-l-carboxylate citrate, and the spasmolytic compound is mg. of diethyl acetyl tropinium methylbromide per tablet.

When administered to a person suifering from cough produced by a cold or upper-respiratory infection, this elfectively suppresses the cough and permits symptomatic relief of the chest symptoms, simultaneously relieving the intestinal spasm which commonly accompanies the use of the antitussive.

The dipropyl acetyl tropinium methylbromide and the dipropyl acetyl ester citrate of tropine are illustrative of a group of synthetic esters of tropine, its salts and quaternary ammonium salts which are described in the pending patent application of Nathan Weiner and Samuel M. Gordon, Serial No. 669,707, filed July 3, 1957, now U.S. Patent No. 2,962,499. The compounds in said pending application have the general formula, in quaternized form:

wherein:

R and R are 'alkyl radicals having 1 to 4 carbon atoms,

R and R designate hydrogen or alkyl radicals having 1 to 4 carbon atoms R designates hydrogen, alkyl, lower aralkyl, e.g., 'benzyl, substituted benzyl, phenethyl and substituted phenethyl radicals, and

X- designates the anion of any suitable, or physiologically or pharmaceutically acceptable acid.

4 The improved compositions of this invention, it will be noted, are basically combinations of an antitussive, preferably a non-addictive one, and a non addictive antispasmodic which is a synthetic ester of tropine or a salt thereof, or a quaternary ammonium salt thereof.

In the combination, the proportions of the spasmolyticto-antitussive can vary from 1:1 to 1:20.

It will be understood that the foregoing description of the invention and the examples set forth are merely illustrative of the principles thereof. Accordingly, the appended claims are to be construed as defining the invention within the full spirit and scope thereof.

I claim:

'1. A composition comprising an antitussive and a spasmolytic, wherein the antitussive is a member of the group consisting of 'dextro-3-methoxy-N-methyl morphinan hydrobromide, noscapine, and Z-(diethylamino-ethoxy) ethyl phenyl-cyclopentyl-l-carboxylate citrate.

2. A composition in accordance with claim 1 wherein the spasmolytic is a member of the group consisting of synthetic esters of tropine, its salts and quaternary ammonium salts.

3. A composition in accordance with claim 1 wherein the antitussive is Z-(diethylamino-ethoxy) ethyl phenylcyclopentyl-l-carboxylate citrate.

4. A composition comprising 5-15 parts of Z-(diethylamino-ethoxy)ethyl phenyl-cyclopentyl-l-carboxylate citrate and 1-2 parts of homatropine methylbromide.

5. A composition comprising 10-20 parts of dextro-3- methoxy-N-methyl morphinan hydrobromide, and 1-3 parts of homatropine methylbromide.

6. A composition comprising 15-25 parts of dextro-3- methoxy-N-methyl morphinan hydrobromide and 3-5 parts of dipropyl acetyl tropinium methylbromide.

7. A composition comprising 10-15 parts of noscapine and 1-3 parts of homatropine methylbromide.

8. A solid composition comprising 10-20 parts of noscapine and 2-10 parts of dipropyl acetyl tropinium methylbromide.

9. A liquid composition comprising 10-20 parts of noscapine and 2-10 parts of dipropyl acetyl tropinium methylbromide.

10. A solid composition comprising 20-30 parts of 2- (diethylamino-ethoxy) ethyl phenyl-cyclopentyl-l-carboxylate citrate and l-4 parts of homatropine methylbromide.

11. A liquid composition comprising 20-30 parts of Z-(diethylamino-ethoxy) ethyl phenyl-cyclopentyl-l-carboxylate citrate and 1-4 parts of homatropine methylbromide.

12. A composition comprising 10-20 parts of 2-(diethylamino-etlroxy) ethyl phenyl-cyclopentyl-l-carboxylate citrate and 3-10' parts of 'dipropyl acetyl ester citrate of tropine.

13. A composition comprising 20-30 parts of 2-(diethylamino-ethoxy) ethyl phenyl-cyclopentyl carboxylate citrate and 3-10 parts of dipropyl acetyl tropinium methylbromide.

References Cited in the file of this patent Jordan: Modern Drug Encyclopedia, seventh edition, 1958, Drug Publications, Inc., New York, N.Y., pages 272 and 1210.

New and Nonoflicial Drugs, 1959, Lippincott Co., Philadelphia, Pa., pages 236, 360 and 361.

Jordan: Modern Drug Encyclopedia, 7th ed., 1958, Drug Publications, New York, N.Y., pages 806 and 807. 

1. A COMPOSITION AN ANTITUSSIVE AND A SPASMOLYTIC, WHEREIN THE ANTITUSSIVE IS A MEMBER OF THE GROUP CONSISTING OF DEXTRO-3-METHOXY-N-METHYL MORPHINAN HYDROBROMIDE, NOSCAPINE, AND 2-(DIETHYLAMINO-ETHOXY) ETHYL PHENYL-CYCLOPENTYL-1-CARBOXYLATE CITRATE. 